Dapagliflozin As Add On Therapy To Insulin Demonstrated Improved Glycemic Control In Patients With Type 2 Diabetes Inadequately Controlled With Insulin

26.06.2010 – 20:45

Orlando, Florida, June 26, 2010 (ots/PRNewswire) - Results from a
24-week Phase 3 clinical study demonstrated that the addition of the
investigational drug dapagliflozin achieved reductions in the primary
endpoint, glycosylated hemoglobin level (HbA1c), in inadequately
controlled type 2 diabetes patients who were treated with insulin
(with or without oral anti-diabetes medications (OADs)), compared to
placebo plus insulin (with or without OADs). The study also
demonstrated that dapagliflozin achieved reductions in the secondary
endpoints that evaluated the change in total body weight from
baseline, change from baseline in mean daily insulin dose, and change
from baseline in fasting plasma glucose (FPG). Generally, adverse
events, serious adverse events and study discontinuations were
similar across all treatment groups. Signs, symptoms and other
reports suggestive of urinary tract and genital infections were more
frequently noted in the dapagliflozin treatment arms compared to
placebo and rarely led to discontinuation. Results from the 24-week
study were presented at the 70th American Diabetes Association (ADA)
Annual Scientific Sessions.
Dapagliflozin, an investigational compound, is a potential
first-in-class sodium-glucose cotransporter-2 (SGLT2) inhibitor
currently in Phase 3 trials under joint development by Bristol-Myers
Squibb Company and AstraZeneca as a once-daily oral therapy for
the treatment of adult patients with type 2 diabetes. SGLT2
inhibitors facilitate the elimination of glucose by the kidney,
which should result in lowering serum glucose levels.
"Many type 2 diabetes patients who are treated with insulin are
not able to achieve their blood sugar goals," said John Wilding, DM,
FRCP, Professor of Medicine and Honorary Consultant Physician, Head
of Diabetes and Endocrinology Clinical Research Unit, University
Hospital Aintree (UK). "The Phase 3 data on glycemic and weight
parameters presented today suggest that further study of
dapagliflozin in this patient population is warranted."
Data from the 48 week follow-up of the same study will be
presented as a late breaker at the ADA Scientific Sessions.
About the Study
The study was a randomized, double-blind, placebo-controlled
study of 800 Individuals with type 2 diabetes (ages 18 - 80) and
inadequate glycemic control whose HbA1c level was greater than or
equal to 7.5% and less than or equal to 10.5% at baseline, with a
mean baseline HbA1c level of 8.5%. The study was designed to assess
the efficacy and safety of dapagliflozin in patients with
inadequately controlled type 2 diabetes receiving treatment with a
mean insulin dose of greater than or equal to 30 IU for at least 8
weeks (mean baseline dose: 77 IU per day) with or without concomitant
OADs. Individuals were equally randomized to one of four separate
treatment groups: dapagliflozin 2.5 mg (n= 202), dapagliflozin 5 mg
(n= 211), dapagliflozin 10 mg (n= 194), or placebo (n= 193).
The primary endpoint of the study compared mean HbA1c change from
baseline for each dapagliflozin treatment arm compared to placebo
after 24 weeks. Secondary endpoints included change in body weight
from baseline, change from baseline in mean daily insulin dose, and
change from baseline in fasting plasma glucose (FPG).
Study Results
After 24 weeks, individuals receiving dapagliflozin 2.5 mg, 5 mg
and 10 mg demonstrated a statistically significant adjusted mean
change in HbA1c from baseline of -0.75%, -0.82% and -0.90%,
respectively, compared to -0.30% for placebo (p-value less than or
equal to 0.0001 for all treatment groups).
The study also evaluated the potential impact of dapagliflozin on
total body weight at week 24. At week 24, the study found that
individuals treated with dapagliflozin demonstrated an adjusted mean
change in total body weight: -0.98 kg for dapagliflozin 2.5 mg, -0.98
kg for dapagliflozin 5 mg and -1.67 kg for dapagliflozin 10 mg,
compared to a weight gain of 0.02 kg for placebo (p-value less than
or equal to 0.0001 for all treatment groups).
Individuals treated with dapagliflozin also demonstrated a
reduction in daily insulin dose at week 24: -1.80 IU/d for
dapagliflozin 2.5 mg, -0.61 IU/d for dapagliflozin 5 mg and -1.16
IU/d for dapagliflozin 10 mg, compared to an increase of 5.08 IU/d
for placebo (p-value less than or equal to 0.0001 for all treatment
groups).
Individuals treated with dapagliflozin demonstrated a reduction
in FPG, a secondary endpoint, from baseline at week 24: -12.5 mg/dL
for dapagliflozin 2.5 mg, -18.8 mg/dL for dapagliflozin 5 mg and
-21.7 mg/dL for dapagliflozin 10 mg, compared to an increase of 3.3
mg/dL for placebo (p-value equal to 0.0008 for dapagliflozin 2.5 mg;
p-value less than or equal to 0.0001 for dapagliflozin 10 mg. (Note
that due to the study testing procedure, the p-value for
dapagliflozin 5 mg could not be assessed).
Generally, adverse events, serious adverse events and study
discontinuations were similar across all treatment groups. The
percentage of patients experiencing the most common adverse events
(greater than or equal to 5 %) for dapagliflozin 2.5 mg, 5 mg 10 mg,
and placebo, respectively are as follows: nasopharyngitis: 13.9%,
13.7%, 8.7%, 11.2%; hypertension: 5.4%, 6.1%, 3.6%, 7.6%; headache:
4.0%, 4.2%, 1.0%, 7.1%; back pain: 4.5%, 1.9%, 4.6%, 5.1%; upper
respiratory tract infection: 2.5%, 2.8%, 3.1%, 5.1%.
The percentage of patients with signs, symptoms and other reports
suggestive of urinary tract and genital infections were higher for
the dapagliflozin treatment arms compared to placebo. Events
suggestive of urinary tract infections were as follows: 5.9%, 7.5%,
7.7% with dapagliflozin 2.5 mg, 5 mg and 10 mg respectively, versus
2.0% with placebo. Events suggestive of genital infections were as
follows: 5.4%, 8.0%, 9.2% with dapagliflozin 2.5 mg, 5 mg and 10 mg
respectively, versus 2.0% with placebo.
Reports of hypoglycemia observed in the dapagliflozin treatment
groups compared to placebo were 55% for dapagliflozin 2.5 mg, 47.6%
for dapagliflozin 5 mg, 44.9% for dapagliflozin 10 mg and 42.1% for
placebo. Of these hypoglycemic events, 1% were major and were equally
distributed across groups.
Reductions in blood pressure were observed without associated
signs of orthostatic hypotension.
About Type 2 Diabetes
Type 2 diabetes (diabetes mellitus) is a complex, progressive
disease characterized by elevated glucose which is frequently
associated with other co-morbidities such as obesity, hypertension
and dyslipidemia. Significant unmet needs exist as nearly half of the
patients remain uncontrolled on their current treatment regimen.
The kidneys play a key but underappreciated role in the overall
regulation of blood glucose levels in the body. Normally, in healthy
individuals, the kidneys filter a large volume of glucose and
actively reabsorb virtually all of it. Glucose reabsorption is
necessary to retain calories, but becomes counterproductive in type 2
diabetes. In patients with type 2 diabetes who have hyperglycemia, a
greater amount of glucose is filtered and reabsorbed by the kidneys,
which contributes to sustained hyperglycemia in diabetes.
Over time, sustained hyperglycemia worsens insulin resistance and
contributes to dysfunction in the beta cells of the pancreas further
undermining control of the disease. Sustained hyperglycemia is also
directly related to diabetic microvascular complications such as
blindness and may also contribute to macrovascular complications.
About SGLT2 Inhibition
The kidney continuously filters glucose through the glomerulus;
however, nearly all of this glucose is reabsorbed. A protein called
SGLT2 is responsible for the majority of glucose reabsorption and
helps the body retain glucose for its energy requirements. For
patients with diabetes, retention of excess glucose by this pathway
contributes to persistent hyperglycemia. Suppressing the activity of
SGLT2 inhibits renal-glucose reabsorption in the body, thereby
leading to the excretion of glucose in the urine.
Bristol-Myers Squibb and AstraZeneca Collaboration
Bristol-Myers Squibb and AstraZeneca entered into a collaboration
in January 2007 to enable the companies to research, develop and
commercialize select investigational drugs for type 2 diabetes. The
Bristol-Myers Squibb/AstraZeneca Diabetes collaboration is dedicated
to global patient care, improving patient outcomes and creating a new
vision for the treatment of type 2 diabetes.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines that
help patients prevail over serious diseases. For more information
about Bristol-Myers Squibb, visit www.bms.com or follow us on Twitter
at http://twitter.com/bmsnews.
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding product development. Such forward-looking statements
are based on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee that
dapagliflozin will receive regulatory approval or, if approved, that
it will become a commercially successful product. Forward-looking
statements in this press release should be evaluated together with
the many uncertainties that affect Bristol-Myers Squibb's business,
particularly those identified in the cautionary factors discussion in
Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended
December 31, 2009, in our Quarterly Reports on Form 10-Q and our
Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement, whether
as a result of new information, future events or otherwise.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical
business with a primary focus on the discovery, development and
commercialization of prescription medicines. As a leader in
gastrointestinal, cardiovascular, neuroscience, respiratory and
inflammation, oncology and infectious disease medicines, AstraZeneca
generated global revenues of $32.8 billion in 2009. In the United
States, AstraZeneca is a $14.8 billion healthcare business.
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ots Originaltext: Bristol-Myers Squibb and AstraZeneca
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CONTACT: Contacts: Media: Ken Dominski, Bristol-Myers
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John Elicker,Bristol-Myers Squibb, +1-609-252-4611,
john.elicker@bms.com; Karl Hard,AstraZeneca, +44-20-7304-5322,
karl.hard@astrazeneca.com; Clive Morris,AstraZeneca,
+44-20-7304-5084, clive.morris@astrazeneca.com